Abstract

Oligodendrocytes are glial cells that populate the entire CNS after they have differentiated from oligodendrocyte progenitor cells. From birth onward, oligodendrocytes initiate wrapping of neuronal axons with a multilamellar lipid structure called myelin. Apart from their well-established function in action potential propagation, more recent data indicate that oligodendrocytes are essential for providing metabolic support to neurons. Oligodendrocytes transfer energy metabolites to neurons through cytoplasmic “myelinic” channels and monocarboxylate transporters, which allow for the fast delivery of short-carbon-chain energy metabolites like pyruvate and lactate to neurons. These substrates are metabolized and contribute to ATP synthesis in neurons. This Review will discuss our current understanding of this metabolic supportive function of oligodendrocytes and its potential impact in human neurodegenerative disease and related animal models.

Authors

Figure 1

Astrocytes (top) can take up glucose from the blood circulation through glucose transporters (GLUT1), a process that is enhanced upon glutamate release from neurons and glutamate binding to astrocyte-expressed glutamate transporters (GLT-1). Glycolysis breaks down glucose to pyruvate with the production of ATP and NADH. Alternatively, astrocytes can break down intracellular glucose, which is stored as glycogen. Subsequently, pyruvate is either metabolized in the mitochondria (leading to additional production of ATP) or converted to lactate by lactate dehydrogenase (LDH) when oxygen is limited (ensuring the continuation of glycolysis through oxidation of NADH to NAD+ to resupply the NAD+ pool). In oligodendrocytes (bottom), glucose can similarly be processed into pyruvate and lactate. Oligodendrocyte glucose uptake is controlled by glutamate binding to the NMDA receptor expressed on the oligodendrocyte surface. Intracellular lactate in astrocytes or oligodendrocytes can either exit the cell through the monocarboxylate transporters MCT1 and MCT4 or be converted back to pyruvate in the mitochondria, where it fuels ATP or fatty acid synthesis. Extracellular lactate can be shuttled to neurons through neuronal MCT2 and used to fuel neuronal ATP synthesis in the mitochondria. Gap junction coupling (Cx) between glial cells and glial cells/neurons mediates the exchange of metabolites like pyruvate and lactate, but the importance of these connections in metabolic shuttling is still to be further explored. Alternatively, it is hypothesized that extracellular lactate is imported in glial cells and could contribute to ATP synthesis in glial cells upon conversion to pyruvate in the mitochondria.